Synthesis of 2,3-anti-3,4-anti and 2,3-anti-3,4-syn propionate motifs: a diastereoselective tandem sequence of Mukaiyama and free-radical-based hydrogen transfer reactions

[reaction: see text] Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of 2,3-anti-3,4-anti and 2,3-anti-3,4-syn propionate motifs. The mode of complexation is controlled through monodentate or chelate pathways for the Mukaiyama reaction to give access to either syn or anti aldol products, precursors of the free-radical reduction reaction. Boron Lewis acid is used to control the free-radical reaction through the exocyclic pathway.     

A dinuclear uranium(IV) complex of the chelating ligand 1,2,3,4‐tetra­methyl‐5‐(2‐pyridyl)­cyclo­penta­diene

The ligand 1,2,3,4‐tetra­methyl‐5‐(2‐pyridyl)­cyclo­penta­diene (cp*py) forms a dinuclear complex with U^IV, i.e. di‐μ‐oxo‐bis­{chloro­(diethyl ether‐κO)[(η⁵,κN)‐1,2,3,4‐tetra­methyl‐5‐(2‐pyridyl)­cyclo­penta­dienyl]uranium(IV)}, [U₂Cl₂O₂(C₁₄H₁₆N)₂(C₄H₁₀O)₂], in which cp*py acts as a chelating ligand, being bound to the metal atom by the cyclo­penta­dienyl unit and also by the N atom of the pyridyl ring.     

Diterpenoids from cultured Erythropodium caribaeorum

The known antimitotic agent eleutherobin and the briarane diterpenoids erythrolides A and B have been isolated from cultured specimens of Erythropodium caribaeorum in amounts comparable to those reported from wild-harvested reef animals. The novel diterpenoid aquariolide A, having an unprecedented highly rearranged carbon skeleton (named aquariane), has also been found. The aquariane skeleton can be formally derived from the briarane skeleton by sequential di-pi-methane and vinyl-cyclopropane rearrangements. [structure: see text]     

Electron affinities of biscyclopentadienyl and phospholyl uranium(IV) borohydride complexes: Experimental and DFT studies

Electron affinities (EAs) of a series of biscyclopentadienyl and phospholyl uranium(IV) complexes L₂U(BH₄)₂ [L₂ = Cp₂, (tmp)₂, (tBuCp)₂, (Cp*)(tmp) and Cp*₂] related to the U(III)/U(IV) redox system were calculated using relativistic Density Functional Theory (DFT) based methods coupled with the Conductor-like Screening Model for Real Solvents (COSMO-RS) approach. Electrochemical measurements of half-wave potentials in solution (tetrahydrofuran THF) were carried out for all these compounds under the same rigorous conditions. A good correlation (r² = 0.99) is obtained between the calculated EA values, at the ZORA/BP86/TZ2P level, and the half-wave reduction potentials measured by electrochemistry. The investigations bring to light the importance of spin-orbit coupling and solvent effect and the use of a large basis set in order to achieve such a good agreement between theory and experiment. The study confirms the instability of the Cp₂U(BH₄)₂ complex during the reduction process. The influence of the substituted aromatic ligand L₂, namely their electron donating ability, on EA was studied. The role of involved orbitals (singled occupied molecular orbital –SOMO– of anionic species or lowest unoccupied molecular orbital –LUMO– of neutral species) in the redox process was revealed.     

Bis‐clickable Mesoporous Silica Nanoparticles: Straightforward Preparation of Light‐Actuated Nanomachines for Controlled Drug Delivery with Active Targeting

Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co‐condensation of TEOS with variable amounts (2–5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on‐demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans‐to‐cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on‐command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin‐loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not.     

An APCI LC‐MS/MS method for routine determination of capecitabine and its metabolites in human plasma

The anticancer drug capecitabine and its metabolites [including the active metabolite 5‐fluorouracil (5‐FU)] display high pharmacokinetic inter‐patient variability. Such variability, which may lead to treatment failure or toxicity, could need drug concentration measurement to individualize dosing regimen. However, usual assay methods are often long and fastidious. A simultaneous and cost‐effective method was thus developed for the determination of the concentrations of these compounds in human plasma. Compounds were extracted via a classic liquid–liquid extraction. Chromatographic analysis was performed on a C18 reverse phase column with detection by atmosphere pressure chemical ionization LC‐MS/MS. Our method allows a good chromatographic separation of the compounds and was fully validated following Food and Drug Administration (FDA) recommendations (good selectivity, no carry‐over, linearity of the calibration curves without weighting, deviations from nominal concentrations of standard samples lower than 15%, intra‐ and inter‐assay precision and accuracy lower than 15%). Recovery and stability were also acceptable following the FDA guidelines. A matrix effect impairing the determination of 5‐FU was avoided by using a stable isotopic derivative of 5‐FU as internal standard. Interestingly, this method allows detection of TetraHydroUridine, an inhibitor of ex vivo degradation of metabolites, which is essential for the stability, the adequate conditioning of blood samples and for good laboratory practice, essential in routine determination. This method seems usable to routinely determine concentrations of capecitabine and its metabolites in blood and may be helpful in further studies aiming at performing therapeutic drug monitoring. Copyright © 2010 John Wiley & Sons, Ltd.     

IR and theoretical studies of monocarbonyl Ni complexes formed by adsorption of CO at low pressure on silica-supported Ni(II) ions

This work reports on the reactivity of coordination vacancies of Ni(II) ions grafted onto the tridentate silica support (Ni(II)(3c) ions) with respect to CO used as a probe molecule. The adsorption of CO at 77 K in the 0.3 to 3.5 Pa CO pressure range is studied by FTIR on two samples differing in the dispersion of nickel. Quantum chemical calculations by the DFT method are performed to investigate, using a cluster approach, the binding of Ni to silica and, after CO adsorption, the geometry of the resulting carbonyl Ni complexes. Silica is modeled by using clusters composed of three types of monodentate ligands, SiO(-), SiOSi and/or SiOH, found on the surface of silica. This work is devoted to the monocarbonyl complexes. Whatever the sample, only one type of monocarbonyl is formed from Ni(II)(3c) ions. It is shown that the charge of the silica cluster is the major parameter influencing the CO IR frequency whereas the nature and the size of the silica cluster do not affect the CO bond length, confirming that local electrostatic interactions predominate. Only the 1- charged silica cluster Si(5)O(3)(-), composed of SiO(-), 2SiOSi fragments, respectively, reproduces the Ni[bond]O distances derived from EXAFS for the Ni(II)(3c) grafted site and gives CO frequencies in good agreement with the experimental values. It is shown that CO is stabilized by a magnetic transition from the (3)Ni(2+) triplet to the (1)Ni(2+) singlet state occurring upon adsorption.     

Aromatization of 1,6,7,7a-tetrahydro-2H-indol-2-ones by a novel process. Preparation of key-intermediate methyl 1-benzyl-5-methoxy-1H-indole-3-acetate and the syntheses of serotonin, melatonin, and bufotenin

Imine 7 of 1,4-cyclohexanedione mono-ethylene ketal 6 was reacted with maleic anhydride, affording the cyclized adduct 8. Methyl esterification of 8, accompanied by transacetalization, led to the dihydrooxindole derivative 10. Aromatization of 10 was then accomplished with POCl(3), leading directly to the key-intermediate title compound 11 in 74% yield from ketone 6. Serotonin, melatonin, and bufotenin were then obtained by standard reactions.